NO341023B1 - Use of 40-O- (2-hydroxyethyl) -rapamycin in carcinoid tumor treatment - Google Patents

Description

The present invention relates to the use of 40-O-(2-hydroxyethyl)-rapamycin as a single drug substance in carcinoid tumor treatment.

40-O-(2-hydroxyethyl)-rapamycin is an mTOR inhibitor and as used herein is a compound that targets intracellular mTOR ("mammalian target of rapamycin"). mTOR is a family member of phosphatidylinositol 3-kinase (P13-kinase) related kinase. The compound rapamycin and other mTOR inhibitors inhibit mTOR activity via a complex with its intracellular receptor FKBP12 (FK506-binding protein 12). mTOR modulates translation of specific mRNAs via the regulation of the phosphorylation state of several different translation proteins, mainly 4E-PB1, P70S6K (p70S6 kinase 1) and eEF2.

The mTOR inhibitor is 40-O-(2-hydroxyethyl)-rapamycin.

mTOR inhibitors, on the basis of observed activity, have been found to be useful e.g. as immunosuppressants, e.g. in the treatment of acute allograft rejection and also have potent antiproliferative properties that make them useful for cancer chemotherapy, especially for the treatment of solid tumors, especially advanced solid tumors.

Endocrine, e.g. neuroendocrine tumors (NETs), are found in the endocrine system. Carcinoid tumors are a special type of tumor, generally classified as endocrine tumors. Carcinoid tumors belong to the family of neuroendocrine tumors that arise from the neuroendocrine cell system. In the digestive tract, these tumors develop deep in the mucosa, grow slowly and expand into the underlying submucosa and the mucosal surface. This results in the formation of small hard nodules that protrude into the intestinal lumen. Pancreatic neuroendocrine tumors (small cell tumors), which were previously classified as APUDomas (tumors of the amine precursor uptake and decarboxylation system), comprise less than half of all neuroendocrine tumors and only 1-2% of all pancreatic tumors. Pancreatic NETs can arise either within the pancreas (insulinomas, glucagonomas, nonfunctioning pancreatic NETs, pancreatic NETs causing hypercalcemia) or at both pancreatic and extrapancreatic sites (gastrinomas, VTPomas, somatostatinomas, GRFomas). The hormones secreted by pancreatic NETs depend on the cell origin and are physiologically involved in a network of autocrine, paracrine, endocrine and neurotransmitter communication. While hormone secretion is not observed in all cases of pancreatic NET, the apparently "nonfunctioning" (ie, nonsecreting) pancreatic NETs tend to be more aggressive and present with symptoms of tumor size (see, e.g., Barakat et al, Endocrine-related cancer 2004;11:1-18, and Tomassetti et al, Ann Oncol 2001;12 (Suppl 2):S95-S99).

All pancreatic NETs, with the exception of 90% of insulinomas, have long-term metastatic potential. Most are overtly malignant at the time of diagnosis and 60% or more present with liver metastases. The most common cause of death from pancreatic NET is liver failure (Warner RRP, Gastroenterology 2005;128:1668-16842005).

In a recent review, the 5-year survival rate in a series of 83 consecutive patients with pancreatic NETs has been reported to be 55.3%, pointing to an unmet medical need for continued treatment in patients with pancreatic NETs 'is whose disease has developed after one or more rounds of chemotherapy.

Carcinoid tumors have historically been classified, according to their point of origin in embryonic development, as arising from the foregut (eg, bronchial, lung, or gastric carcinoid), in the midgut (eg, small bowel or cecal carcinoid), or hindgut (e.g. rectal carcinoid), see e.g. Kulke M., Cancer Treatment Reviews 2003;29:363-370.

Primary tumors from the early intestine are limited to the thymus, lung, stomach and duodenum. Midgut carcinoids are located in the distal ileum, cecum and near colon. An interesting subset of this group are appendiceal carcinoids, which are often benign and rarely give rise to metastatic disease. Midgut carcinoids dominate the malignant carcinoid tumors, especially when the carcinoid syndrome is present.

Tumors in the hindgut are primarily located in the distant colon and rectum.

According to histological criteria, carcinoids can be divided into typical (TC) and atypical (AC) carcinoids. Carcinoids can be placed in a spectrum of neuroendocrine tumors, ranging from low-grade malignant TC to intermediate AC to high-grade large cell neuroendocrine carcinoma and small cell lung carcinoma.

Carcinoid tumors of the GI system may show an aggressive biology similar to that of adenocarcinomas, especially when located in the colon, stomach and small intestine, see e.g. Modlin IM et al, Gastroenterology 2005;128:1717-1751. For small bowel carcinoids, which are the most frequent cause of carcinoid syndrome due to metastatic disease in the liver, the incidence of metastasis increases proportionally with the size of the primary tumor (Tomassetti et al 2001, ibidem).

Available incidence and survival data suggest that clinical trials of new anticancer agents in patients with midgut carcinoid tumors may provide the opportunity to investigate an unmet medical need in a growing portion of the carcinoid patient population.

Carcinoid syndrome is caused by hypersecretion of several hormone products by the tumor cells, including kinins, prostaglandins, substance P, gastrin, corticotrophin, and chromogranin A (see, e.g., Davis et al, Gynecology & Obstetrics 1973;137:637-644). Various endocrine or neuroendocrine syndromes may be initial clinical manifestations of either typical or atypical lung carcinoid tumors. Carcinoid syndrome, hypercortisolism and Cushing syndrome, inappropriate secretion of ADH, increased pigmentation secondary to excess MSH and ectopic insulin production resulting in hypoglycemia are some of the endocrinopathies that can be produced by a pulmonary carcinoid tumor in an otherwise asymptomatic patient.

The most common symptoms are whooping cough, cough, recurrent lung infection, fever, chest discomfort and chest pain, one-sided heavy breathing and shortness of breath, flushing and diarrhoea. Paraneoplastic syndromes are rare and include carcinoid syndrome, Cushing's syndrome, and ectopic growth hormone-releasing hormone secretion.

Other less common symptoms include cardiac manifestations secondary to fibrosis of the endocardium (Jacobsen MB et al, Eur Heart J 1995;16:263-268) which may result in valve regurgitation (valvular heart disease), with varying degrees of heart failure in patients with cardiac manifestations. Dyspnea or asthma-like symptoms, pellagra-like skin lesions with hyperkeratosis, abdominal pain, telangiectasia and paroxysmal hypotension are also seen in a number of patients. Patients with pulmonary carcinoid often show symptoms such as recurrent pneumonia, cough, hemoptysis or chest pain. The majority of lung carcinoid tumors are in the perihilar area. Ectopic secretion of corticotropin from lung carcinoid tumors can also be the cause of Cushing's syndrome. Early in the course, the symptoms are usually episodic and can be triggered by stress, catecholamines and the consumption of food or alcohol. During acute attacks, systolic blood pressure usually falls 20 to 30 mmHg. Endocardial fibrosis can cause valvular heart disease, which usually affects the proximal side of the tricuspid and pulmonary valves and leads to tricuspid insufficiency and secondary right-sided heart failure.

A recent review of chemotherapeutic treatment of carcinoids reports that the sensitivity of these tumors to different cytotoxic drugs is low, and combination does not increase their effectiveness. Based on their review of different combination therapies, which include dacarbazine/fluorouracil or 5-fluorouracil/epirubicin, the authors conclude that they are unable to recommend a specific chemotherapeutic regimen for patients with well-differentiated neuroendocrine malignancies of the GI tract (Arnold R, Rinke A et al, Clinical Gastroenterology 2005;19(4):649-656). The apparent refractoriness of such tumors to currently available therapies points to an unmet medical need for treatment in this patient population.

Multiple endocrine neoplasia type 1 (MEN 1) is a relatively uncommon hereditary disease. Individuals who inherit the gene for MEN 1 have an increased chance of developing overactivity and enlargement of certain endocrine glands. The endocrine glands most often affected by MEN 1 are the parathyroid, pancreas and pituitary glands. Almost everyone who inherits MEN 1 develops overactivity of the parathyroid glands (hyperparathyroidism) at some stage in their lives. The other endocrine glands become overactive less often, however, people who inherit MEN 1 will usually develop overactivity in more than one endocrine gland. Overactivity in different endocrine glands can occur simultaneously or at different times during a person's life. MEN 1 can lead to overactivity and enlargement of the three endocrine glands mentioned above (the endocrine glands that start with the letter "p"). People who inherit the gene for MEN 1 are predisposed to develop an overactivity in hormone production from the parathyroid glands, pituitary gland and pancreas (this is why doctors will measure hormones in the blood to check for overproduction of each specific hormone). Increased hormone production is usually associated with enlargement of these glands. Endocrine gland enlargement and hormone overproduction do not usually occur in all areas of an endocrine gland at the same time. Some parts of overactive endocrine glands grow faster than others, and produce more hormone than other parts of the same gland. The parts of a growing endocrine quickly become "lumpy". These lumps are usually benign. Benign lumps in endocrine glands are known as adenomas.

Adenomas are benign (they are not cancerous) and do not spread to other parts of the body. It was found that 40-O-(2-hydroxyethyl)-rapamycin can be used as a single active ingredient for treating carcinoid tumors arising from the anterior, middle or posterior intestine.

According to the particular findings, the present invention provides several aspects: 1. 40-O-(2-hydroxyethyl)-rapamycin for use as a single drug substance in the treatment of carcinoid tumors arising from the anterior, middle or posterior intestine. 2. A pharmaceutical composition comprising 40-O-(2-hydroxyethyl)-rapamycin in combination with at least one pharmaceutically acceptable excipient for use in the treatment of carcinoid tumors arising from the foregut, middle or hindgut.

The at least one pharmaceutically acceptable excipient can e.g. be a suitable carrier and/or diluent, such as e.g. include fillers, binders, disintegrants, flow aids, lubricants, sugars or sweeteners, flavorings, preservatives, stabilizers, softeners and/or emulsifiers, solvents, salts to regulate osmotic pressure and/or buffers.

Endocrine tumors as indicated here include carcinoid tumors.

Carcinoid tumors as indicated here include common and uncommon carcinoids; as

e.g. includes carcinoids arising from

the foregut, e.g. bronchial, lung or stomach carcinoids, such as includes primary tumors of the foregut limited to the thymus, lung,

stomach and duodenum; e.g. carcinoid tumors of the GI system, e.g. located in the colon, stomach or small intestine, e.g. small bowel carcinoids, e.g. which includes

middle intestine, e.g. small bowel or appendix carcinoids, e.g. located in

the distal ileum, cecum and proximal colon, or

hind gut, e.g. rectal carcinoids.

Endocrine or neuroendocrine tumor symptoms as indicated here include e.g. coughing up blood, coughing, recurrent lung infection, fever, chest discomfort and chest pain, unilateral wheezing, shortness of breath, flushing and diarrhoea, endocrine or neuroendocrine syndromes carcinoid syndrome, such as include manifestation of either common or uncommon pulmonary carcinoid tumors, Cushing's syndrome, inappropriate secretion of ADH, increased pigmentation secondary to excess MSH, and ectopic insulin production resulting in hypoglycemia, ectopic growth hormone-releasing hormone secretion, ectopic secretion of corticotropin, cardiac manifestations secondary to fibrosis of the endocardium (endocardial fibrosis ), valvular regurgitation (valvular heart disease), tricuspid insufficiency, secondary right-sided heart failure, wheezing or asthma-like symptoms, pellagra-like skin lesions with hyperkeratosis, abdominal pain, telangiectasia and paroxysmal hypotension, recurrent pneumonia, cough, chest pain.

Where previously and hereinafter a tumor, a tumor disease, a carcinoma or a cancer is mentioned, metastases in the original organ or tissue and/or in any other location are also covered alternatively or in addition, regardless of the location of the tumor and/or the metastasis has.

Disorders associated with endocrine tumors include endocrine or neuroendocrine tumor symptoms, as indicated above. Disorders include diseases.

40-O-(2-hydroxyethyl)-rapamycin can be used alone or with one or more, at least one, pharmaceutically acceptable excipient.

Treatment of disorders (diseases) according to the present invention includes prophylaxis (prevention).

For such treatment, the appropriate dose will of course vary, depending, for example, on the chemical nature and pharmacokinetic data of a compound used, the individual host, the mode of administration, and the nature and severity of the conditions being treated. However, in general, to obtain satisfactory results in larger mammals, such as humans, an indicated daily dose includes a range

from 0.0001 g to approx. 1.5 g, such as 0.001 g to 1.5 g;

from 0.001 mg/kg body weight to 20 mg/kg body weight, such as 0.01 mg/kg body weight to 20 mg/kg body weight,

for example, administered in divided doses up to four times per day.

40-O-(2-hydroxyethyl)-rapamycin for use as a single active ingredient in the treatment of carcinoid tumors arising from the foregut, mid or hindgut, or pharmaceutical composition provided by the present invention, may be administered as appropriate, e.g. . at doses known for 40-O-(2-hydroxyethyl)-rapamycin, by any route of administration, e.g. enterally, e.g. orally, or parenterally. For example, everolimus can be administered, e.g. orally, in doses from 0.1 mg up to 15 mg, such as 0.1 mg to 10 mg, e.g. 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2.5 mg, 5 mg or 10 mg, more desirably from 0.5 mg to 10 mg, e.g. in the form of (soluble)

pills; e.g. comprising everolimus in the form of a solid dispersion; e.g. a weekly dose may include up to 70 mg, e.g. 10 to 70, such as 30 to 50 mg, depending on the disease to be treated.

Pharmaceutical compositions according to the present invention can be produced according to, e.g. analogously, a method which is conventional, e.g. by mixing, grinding, coating, dissolving or freeze-drying. Unit dosage forms may contain, for example, from 0.1 mg to 1500 mg, such as 1 mg to 1000 mg.

In another preferred aspect, the present invention provides any pharmaceutical composition or use of 40-O-(2-hydroxyethyl)-rapamycin as a sole active ingredient for treating carcinoid tumors arising from the foregut, mid or hindgut.

Carcinoid tumor treatment with 40-O-(2-hydroxyethyl)-rapamycin as indicated herein may be associated with radiation therapy. Carcinoid tumor treatment with 40-O-(2-hydroxyethyl)-rapamycin as a single active ingredient may be a second-line treatment, e.g. after treatment with another anticancer drug.

In each case where citations of patent applications or scientific publications are given, likewise the pharmaceutically acceptable salts thereof, the corresponding racemates, diastereoisomers, enantiomers, tautomers as well as the corresponding crystal modifications of the above-explained compounds where they exist present, e.g. solutions, hydrates and polymorphs, which are elaborated therein, included.

The structure of the drug substances identified by code numbers, generic or trade names can be taken from the Internet, real edition of the standard compendium "The Merck Index"

or from databases, e.g. Patents International, e.g. IMS World Publications, or the publications mentioned above and below.

The use of 40-O-(2-hydroxyethyl)-rapamycin as a single active ingredient in the treatment of carcinoid tumors arising from the foregut, middle or hindgut specified above can be demonstrated in vitro, in animal test procedures as well as in the clinic , for example according to the methods that will be described below.

A. In vitro

A. l Antiproliferative activity in combination with other agents

A cell line, e.g. the compound A resistant A549 line (IC50i low nM range) versus the comparative compound A resistant KB-31 and HCT116 line (IC50i micromolar range), are added to 96-well plates (1500 cells/well in 100 µl medium) and incubated for 24 hours. Then, a two-fold dilution series of each compound (an mTOR inhibitor different from compound A or a known chemotherapeutic agent) was made in separate tubes (starting at 8 x IC50 for each compound) either alone or in paired combinations, and the dilutions added to the wells.

The cells were then reincubated for 3 days. Methylene blue staining is performed on day 4 and the amount of bound dye (proportional to the number of surviving cells binding to the dye) is determined. The IC50 is then determined using the Calcusyn program, which provides a measure of the interaction, namely the so-called non-exclusive combination index (CI), where: CI~1 = the interaction is nearly additive;

0.85-0.9 = slight synergism; < 0.85 = synergy. In this analysis, mTOR inhibitors, e.g. compound A, interesting antiproliferative activity in combination with another chemotherapeutic agent, e.g. as defined above, e.g. in combination with somastatin or a somastatin analogue.

B. In vitro analysis

The phosphorylation status of downstream markers S6 (the inhibitor of S6K1 activity) is used as a readout, and reflects the immediate pharmacodynamic effect of the mTOR inhibitor, e.g. in the p70S6 kinase 1 (S6K1) analysis, see e.g. WO2005064343. Carcionoid power can be determined by measuring chromogranin A which, among other things, is hypersecreted in carcionoid cells, see e.g. Davies et al, Gynecology & Obstetrics 1973; 137:637-644.

C. In vitro studies

Compound A is capable of regaining the activity of endocrine agents, such as estrogen inhibitors and/or aromatase inhibitors in cells that are otherwise resistant to endocrine agent treatment. Several studies have indicated aberrant activity of the Akt kinase as a significant mechanism by which breast cancer tumors do not respond to endocrine therapy.

D. Clinical trials

In clinical trial studies involving patients with carcinoid or small cell cancer, inhibition of S6K1 activity and a reduction of chromogranin A can be observed when either compound A is given alone or a combination of Sandostatin LAR® (30 mg daily) and compound A (5 mg daily). Response evaluation can be performed every 12 weeks. Duration of study: 6 months).

Synergistic effects of such a combination are also obtained.

Further clinical studies using compound A in an amount of 5 mg or 10 mg daily (5 to 70 mg weekly) in monotherapy, and in combination therapy together with e.g.

30 mg of Sandostatin LAR® daily is being investigated, for example.

A randomized, double-blind, placebo-controlled study of compound A in 420 patients receiving therapy with Sandostatin LAR® for advanced midgut carcinoid tumors. Patients continue baseline Sandostatin LAR® therapy and are randomized to receive compound A 10 mg/day or placebo. Primary endpoint is progression free survival (PFS). Secondary endpoints include overall survival, carcinoid-associated symptoms of flushing and diarrhea, pharmacokinetics and pharmacodynamics. For efficacy assessment progression and response are assessed per RECIST criteria. Due to the nature of neuroendocrine tumors, all patients must have triphasic CT scans or MRI. Scans are repeated every two months. Purpose: Compound A in combination with Sandostatin LAR® for the treatment of advanced progressive middle arm tumor (carcinoid tumor).

A single-arm placebo-controlled study of compound A 10 mg/day in 100 patients with measurable advanced (metastatic or unresectable) pancreatic neuroendocrine tumors (small cell tumor) after failure of cytotoxic chemotherapy as a monotherapy. Primary objective is to determine the response rate. A group of 44 patients receiving chronic treatment with Sandostatin LAR® for secretory pancreatic tumors were also treated with compound A, 10 mg per day, in addition to Sandostatin

LAR®.

Claims (4)

1. 40-O-(2-hydroxyethyl)-rapamycin for use as a single drug substance in the treatment of carcinoid tumors arising from the foregut, midgut or hindgut. 2. 40-O-(2-hydroxyethyl)-rapamycin for use according to claim 1, wherein carcinoid tumors are tumors of the gastrointestinal tract. 3. 40-O-(2-hydroxyethyl)-rapamycin for use according to claim 2, wherein the tumor arises from the middle or hind intestine. 4. A pharmaceutical composition comprising 40-O-(2-hydroxyethyl)-rapamycin in combination with at least one pharmaceutically acceptable excipient for use in treatment according to any one of claims 1 to 3.